RU2460294C9 - Method of control of zooparasites - Google Patents

Abstract

FIELD: agriculture.

SUBSTANCE: invention relates to means of control of zooparasites. The product contains N-arilpirazole of general formula

, where R¹ and R³ independently mean halogen, R² means haloalkyl of 1-3 carbon atoms, R⁴ means a cyanogroup or -C(=S)NH₂. The means additionally comprises an aliphatic cyclic carbonate, an aliphatic acyclic polyether which is a derivative of diols having up to 8 carbon atoms, and pharmaceutically acceptable auxiliary or supplementary materials. It is used for manufacture of a medicinal product.

EFFECT: invention enables to improve the effectiveness and safety of the means.

6 cl, 3 tbl, 5 ex

Description

The invention relates to new means of combating parasites of animals containing arylpyrazole in the formulation, including aliphatic cyclic carbonates.

Arylpyrazoles, as well as their effectiveness as insecticides and acaricides, are known from the publications of international, European and national applications US 2006014802 A1, WO 2005090313 A1, FR 2834288 A1, WO 09828277, US 06069157, WO 200031043, DE 19824487, WO 098045903, WO 09994590, WO 09994590, WO 099945303, WO 099845303, WO 099945903, WO 09994590, WO 09994590, WO 099945903, WO 099945903, WO 099945903, WO 099945903, WO 09994590, WO 099945903, WO 099945903, WO 09994590, WO 099945903, WO 09994590, WO 09994590, WO 09994590, WO 09994590, WO 0999,590,330 EP 00933363, EP 00911329, WO 09856767, US 05814652, WO 09845274, WO 9840359, WO 09828279, WO 09828278, DE 19650197, WO 09824767, EP 00846686, EP 00839809, WO 097286386, WO 097286386, WO 09728636, , US 05556873, EP 00659745, US 05321040, EP 00511845, EP-A-234119. EP-A-295117 and WO 98/24769. Despite this plethora of applications, where various structures with arylpyrazole are given, there is one predominant type of structure that shows the greatest effectiveness compared to others when used for most indications. It is generally recognized that the most effective compound for controlling most parasites in this class is 1- [2,6-dichloro-4- (trifluoromethyl) phenyl] -3-cyano-4 - [(trifluoromethyl) sulfinyl] -5-aminopyrazole (international generic name “fipronil”).

Arylpyrazoles have been on the ectoparasite market for more than 10 years (Hunter, JS, Ill, DM Keister and P. Jeannin. 1994. Fipronil: A new compound for animal health. Proc. Amer. Assoc. Vet. Parasitol. 39th Ann. Mtg San Francisco, CA. Pg. 48.). They are characterized by high efficiency, its wide range and acceptable tolerance. Available formulations with a high proportion of DEE (transcutol) contain a strong transdermal component (FR 1996-11446 A; safety certificate: ISO / DIS 11014/29 CFR 1910.1200 / ANSI Z400.1 print date 10/23/2001: FRONTLINE® TOP SPOT ™: fipronil 9.7% w / w). Thus, through the formulation, it facilitates penetration into the sebaceous glands and into the epithelium layers (Skin distribution of fipronil by microautoradiography following topical administration to the beagle dog. Co-chet, Pascal; Birckel, P .; Bromet-Petit, M .; Bromet, N .; Weil, A .; European Journal of Drug Metabolism and Pharmacokinetics (1997), 22 (3), 211-216.). A high concentration in the sebaceous glands can contribute to the long-term availability of the active substance through the excretion of sebum (if the excretion of the active substance takes place with it). In the case of the usual formulations, however, the penetration of arylpyrazoles into the bloodstream is also likely, since a blood vessel approaches each hair follicle and the follicle is separated from the bloodstream by only a thin barrier (Transfollicular drug delivery - Is it a reality? (Transfollicular drug delivery - reality is it? ”) Meidan, Victor M .; Bonner, Michael C .; Michniak, Bozena B .; International Journal of Pharmaceutics (2005), 306 (1-2), 1-14). Thus, the availability of the active substance in the animal is also limited in time and concentration, since the active substance enters the bloodstream and thus reduces the available concentration in the sebum.

The manifestations of this weakness of the currently known formulations must be limited, for which they changed the basic properties of the formulation, without losing, however, in favorable performance indicators. After carrying out intensive analytical and experimental measures for these purposes on a number of additives, solvents and agents that promote distribution (over the skin surface), an additive was unexpectedly identified that can improve the performance of arylpyrazoles in the destruction of arthropods.

The invention relates to new means of combating parasites of animals containing arylpyrazole in the formulation, including:

- aliphatic cyclic carbonate

- aliphatic cyclic or acyclic polyether

The arthropod control agents according to the invention are new and, compared with the formulations described previously, have significantly improved and longer lasting efficacy, while increasing safety for the person using them and for the animal receiving the agent.

Arylpyrazoles as active substances for the control of arthropods ("arthropodicides") are known per se to the specialist, for example, from the above documents, which are hereby referred to.

Preferred phenylpyrazoles are those of formula (I):

where X is N- or CR ¹

R ¹ and R ³ independently from each other mean halogen,

R ² means halogen, halogenated with 1-3 carbon atoms, S (O) _n CF ₃ or SF ₅

n means 0.1 or 2

R ⁴ means hydrogen, cyano or a residue with the formula:

or one of the following cyclic substituents:

R ⁵ means hydrogen, alkynyl with 2-4 carbon atoms, alkenyl with 2-4 carbon atoms, which, if necessary, can be substituted once or repeatedly by substituents such as halogen or alkyl with 1-3 carbon atoms, or R ⁵ means - ( C = O) -alkyl with 1-4 carbon atoms, -S-alkyl with 1-4 carbon atoms, -S-haloalkyl with 1-4 carbon atoms, -S (= O) -alkyl with 1-4 carbon atoms or -S (= NH) -alkyl with 1-4 carbon atoms, optionally substituted with halogen phenyl, optionally substituted with halogen furyl, residue -NR ¹⁴ R ¹⁵ , oxiranyl residue, which at if necessary, it can be substituted once or repeatedly by substituents such as alkyl with 1-4 carbon atoms or halogenated alkyl with 1-4 carbon atoms, or the cyclopropyl residue, which if necessary can be substituted once or repeatedly by such substituents as halogen, alkyl with 1-4 carbon atoms carbon or halogenated with 1-4 carbon atoms,

R ⁶ means hydrogen, alkylcarbonyl with 1-4 carbon atoms or the residue —NR ¹⁶ R ¹⁷ .

R ⁷ means hydrogen, alkyl with 1-4 carbon atoms, -S-alkyl with 1-4 carbon atoms or -NR ⁹ R ¹⁰ ,

Y means = S, = O, = NH, = N-alkyl with 1-4 carbon atoms, = N-OH, or

R ⁸ means alkyl with 1-4 carbon atoms,

R ⁹ and R ¹⁰ independently from each other mean hydrogen, hydroxy-group or alkyl with 1-4 carbon atoms,

R ¹¹ means hydrogen, alkyl with 1-4 carbon atoms, -COO-alkyl with 1-4 carbon atoms or -CONR ¹² R ¹³ ,

R ¹² and R ¹³ independently from each other mean hydrogen or alkyl with 1-4 carbon atoms,

R ¹⁴ and R ¹⁵ independently from each other mean hydrogen, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms, or -SO ₂ -alkyl with 1-4 carbon atoms,

R ¹⁶ and R ¹⁷ independently from each other mean hydrogen, alkoxygroup with 1-4 carbon atoms or alkyl with 1-4 carbon atoms, and alkyl with 1-4 carbon atoms can be substituted if necessary, and phenyl, pyrazinyl act as substituents or pyridyl, wherein phenyl, pyrazinyl or pyridyl can be substituted once or repeatedly, and substituents are hydroxy, alkyl with 1-4 carbon atoms, haloalkyl with 1-4 carbon atoms and / or alkoxy with 1-4 carbon atoms, or

R ¹⁶ and R ¹⁷ mean alkylcarbonyl with 1-4 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms, alkoxyalkylcarbonyl with 1-4 carbon atoms in the alkoxy group and 1-4 carbon atoms in the alkylcarbonyl or the remainder is (C = O) NR ²⁰ R ²¹ , or

R ¹⁶ and R ¹⁷ together mean a group = CR ¹⁸ R ¹⁹ associated with a nitrogen double bond,

R ¹⁸ and R ¹⁹ independently of each other mean phenyl, which, if necessary, once or repeatedly substituted by substituents such as hydroxy, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms and / or alkoxy group with 1-4 carbon atoms, and / or R ¹⁸ and R ¹⁹ mean hydrogen, alkyl with 1-4 carbon atoms, alkenyl with 1-4 carbon atoms or alkoxy group with 1-4 carbon atoms, moreover, alkyl with 1-4 carbon atoms, alkenyl with 1-4 atoms carbon or alkoxygroup with 1-4 carbon atoms, if necessary, can be replaced by phenyl, which in turn, if necessary, once or repeatedly substituted by substituents such as hydroxy, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms and / or alkoxy group with 1-4 carbon atoms,

R ²⁰ and R ²¹ independently from each other mean hydrogen, alkyl with 1-4 carbon atoms or phenyl, which, if necessary, once or repeatedly substituted by substituents such as hydroxy, alkyl with 1-4 carbon atoms, halogenated with 1-4 carbon atoms and / or alkoxy group with 1-4 carbon atoms,

R ²² means alkyl with 1-4 carbon atoms,

Halogen preferably means fluoro, chloro, bromo or iodo, especially fluoro, chloro, bromo.

Alkyl with 1-4 carbon atoms means straight-chain or branched alkyl having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

Haloalkyl with 1-4 carbon atoms means straight-chain or branched alkyl having from 1 to 4 carbon atoms, which is connected to one or more identical or different halogen atoms; this also includes perhalogen-alkyl compounds. Fluoroalkyls are preferred. Examples are —CF ₂ H, —CF ₃ , —CH ₂ CF ₃ , —CF ₂ CF ₃ .

Preferably, the substituents mean the following:

X preferably means CR ¹ .

R ¹ and R ³ preferably independently of one another are chloro or bromo.

R ² preferably means halogenated with 1-3 carbon atoms or SF ₅ .

R ⁴ preferably means hydrogen, a cyano group or a residue with the formula:

or one of the following cyclic substituents:

R ⁵ preferably means hydrogen, alkynyl with 2-3 carbon atoms, alkenyl with 2-3 carbon atoms, which may optionally be substituted once with substituents such as halogen or alkyl with 1-3 carbon atoms, or R ⁵ preferably means - ( C = O) -alkyl with 1-4 carbon atoms, -S-alkyl with 1-3 carbon atoms, -S-haloalkyl with 1-3 carbon atoms, -S (= O) -alkyl with 1-3 carbon atoms or -S (= NH) alkyl with 1-3 carbon atoms, optionally substituted with halogen, phenyl optionally substituted by halogen furyl residue -NR ¹⁴ R ¹⁵ residue oxireno neela, optionally substituted haloalkyl of 1-3 carbon atoms, or a cyclopropyl residue, which can optionally be mono- or polysubstituted by substituents such as halogen, alkyl having 1-4 carbon atoms or halogenoalkyl with 1-4 carbon atoms,

R ⁶ preferably means hydrogen, an alkylcarbonyl of 1 to 3 carbon atoms, or the residue is NR ¹⁶ R ¹⁷ .

R ⁷ preferably means hydrogen, alkyl with 1-4 carbon atoms, —S-alkyl with 1-4 carbon atoms or —NR ⁹ R ¹⁰ ,

Y preferably means = S, = O, = NH, = N-OH, or

R ⁸ preferably means alkyl with 1-3 carbon atoms,

R ⁹ and R ¹⁰ independently from each other preferably mean hydrogen, hydroxy-group or alkyl with 1-3 carbon atoms,

R ¹¹ preferably means hydrogen, alkyl with 1-4 carbon atoms or CONR ¹² R ¹³ ,

R ¹² and R ¹³ independently from each other preferably mean hydrogen or alkyl with 1-3 carbon atoms,

R ¹⁴ and R ^15, independently of one another, are preferably hydrogen, alkyl with 1-3 carbon atoms, haloalkyl with 1-3 carbon atoms or alkyl with 1-3 carbon atoms and an —SO ₂ group;

R ¹⁶ and R ¹⁷ independently from each other preferably mean hydrogen, an alkoxy group with 1-3 carbon atoms or alkyl with 1-3 carbon atoms, and alkyl with 1-3 carbon atoms can be substituted if necessary, and phenyl acts as substituents, pyrazinyl or pyridyl, wherein phenyl, pyrazinyl or pyridyl can be substituted once or twice, and hydroxy, alkyl with 1-3 carbon atoms, haloalkyl with 1-3 carbon atoms and / or alkoxy group with 1-3 carbon atoms serve as substituents

or

R ¹⁶ and R ¹⁷ mean alkylcarbonyl with 1-4 carbon atoms, alkoxycarbonyl with 1-4 carbon atoms, alkoxyalkylcarbonyl with 1-4 carbon atoms in the alkoxy group and 1-4 carbon atoms in the alkylcarbonyl or the residue = (C = O) NR ²⁰ R ²¹ , or

R ¹⁶ and R ¹⁷ together mean a group = CR ¹⁸ R ¹⁹ associated with a nitrogen double bond,

R ¹⁸ and R ^19, independently of one another, preferably mean phenyl, which is optionally substituted once or twice with substituents such as hydroxy, alkyl with 1-3 carbon atoms, halogenated with 1-3 carbon atoms and / or alkoxy with 1-3 carbon atoms and / or R ¹⁸ and R ¹⁹ mean hydrogen, alkyl with 1-3 carbon atoms, alkenyl with 1-3 carbon atoms or alkoxy group with 1-3 carbon atoms, and alkyl with 1-3 carbon atoms, alkenyl with 1 -3 carbon atoms or an alkoxy group with 1-3 carbon atoms can be substituted if necessary enyl, which in turn is optionally substituted once or twice with substituents such as hydroxy, alkyl with 1-4 carbon atoms, haloalkyl with 1-4 carbon atoms and / or alkoxy with 1-4 carbon atoms,

R ²⁰ and R ^21, independently of one another, are preferably hydrogen, alkyl with 1-3 carbon atoms or phenyl, which is optionally substituted once or twice with substituents such as hydroxy, alkyl with 1-3 carbon atoms, halogenated with 1-3 carbon atoms and / or alkoxygroup with 1-3 carbon atoms,

R ²² preferably means alkyl with 1-3 carbon atoms.

Particularly preferred meanings of the substituents in the formula (I) are as follows:

X is CR ¹ .

R ¹ and R ³ in each case mean Cl.

R ² means CF ₃ .

R ⁴ is CN, —C (═S) NH ₂ or —C (═O) CH ₃ .

R ⁵ means —SCHF ₂ , —S (= O) CF ₃ , —S (= O) CH ₃ , —S (= O) CH ₂ CH _3, or a residue

1-trifluoromethyloxyranyl.

R ⁶ means an amino group or one of the following residues:

The following are preferred examples of compounds that can be used according to the invention:

Particularly preferred examples of compounds that can be used according to the invention are as follows:

An example of highly preferred N-arylpyrazole is fipronil.

Another example of highly preferred N-arylpyrazole is 5-amino-4-trifluoromethylsulfinyl-1- (2,6-dichloro-4-trifluoromethyl-phenyl) -3-thiocarbamoylpyrazole.

Depending on the type and location of the substituents, the active substances may take the form of various stereoisomers, in particular enantiomers and racemates. Both pure stereoisomers and mixtures thereof can be used according to the invention.

If necessary, it is possible to use the active substances in the form of salts, moreover, acid addition salts and basic salts suitable for use in pharmaceuticals can be used.

Salts of mineral acids or organic acids (for example, carboxylic or sulfonic acids) can be used as pharmaceutically acceptable salts. Examples include salts of hydrochloric acid, sulfuric acid, acetic, glycolic, lactic, succinic acid, citric, tartaric, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic, gluconic, embonic, glutamic or aspartic acid. As examples of pharmaceutically acceptable basic salts, alkaline salts, for example sodium or potassium salts, alkaline earth metal salts, for example magnesium or calcium salts, should be mentioned.

In addition, the active substances can also be used in the form of solvates, in particular hydrates. By solvates are meant both solvates, in particular hydrates of the active substances themselves, and solvates, in particular hydrates of their salts.

Active substances as solids under certain circumstances are able to form various crystalline modifications. For use in pharmaceutical preparations, stable modifications with appropriate solubility indicators are beneficial.

Unless otherwise indicated, percentages are by weight percent based on the weight of the finished formulation.

The agents contain arylpyrazole, usually in amounts from 1 to 27.5% by weight, preferably from 5 to 20% by weight, and particularly preferably from 7.5 to 15% by weight.

The aliphatic cyclic carbonate is preferably ethylene carbonate or propylene carbonate, and mixtures are also possible.

The amount of aliphatic cyclic carbonate in the formulation may vary from 10 to 70% by weight, preferably from 12.5 to 50% by weight, and particularly preferably from 15 to 40% by weight.

Aliphatic cyclic and / or acyclic ethers are compounds known per se. It is preferably ethers derived from diols having up to 8 carbon atoms, examples of which are ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol. In acyclic ethers, one or both hydroxyl groups carry an alkyl group with 1-4 carbon atoms, preferably only one group being esterified. Preferred examples include: diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, dipropylene glycol monopropyl ether. Preferred 5- or 6-membered cyclic ethers have one oxygen atom and 4 or 5 carbon atoms in the ring and, if necessary, carry an alkyl substituent with 1-4 carbon atoms; preferably, they carry a hydroxyl group either directly on the ring or on an alkyl substituent with 1-4 carbon atoms. A particularly preferred example is tetrahydrofurfuryl alcohol. In the means according to the invention, the amount of aliphatic cyclic and / or acyclic ether can vary widely from 20 to 77.5 wt. -%, and the amount in the range from 25 to 65 wt. particularly preferred, and amounts ranging from 25 to 50% of the mass. highly preferred.

According to a preferred embodiment, the agents according to the invention may further comprise one or more esters of a dihydric or trihydric alcohol having at least three carbon atoms with organic fatty acids of 6-18 carbon atoms. The esters used according to the invention contain, as an alcohol component, a diatomic or triatomic alcohol having up to three carbon atoms, such as, for example, ethylene glycol, propylene glycol or glycerin. Typically, at least two, and preferably all, hydroxyl groups of the alcohol are esterified. The acidic components of esters are fatty acids with 6-18 carbon atoms, which can be straight chain, branched, and also once or repeatedly unsaturated. Mixed esters or mixtures of various types of esters can also be used. As triglycerides, caprylic and capric acid triglycerides, as well as caprylic, capric and linoleic acid triglycerides are preferred. Equally preferred are propylene glycol esters with caprylic and / or capric acid (propylene glycol octanoate decanoate). It is particularly preferred that these esters of glycerol or propylene glycol with caprylic / capric acid have a viscosity in the range (at 20 ° C.) of 0.08-1.3 Pa * s, more preferably, however, 0.08-0.40 Pa * from. It is also possible to use their derivatives modified with polyethylene oxide, polypropylene oxide and / or propylene carbonate, whose viscosity is in the specified range. Examples include propylene glycol dicaprilate, propylene glycol octanoate decanoate with a viscosity range of 0.09-0.12 Pa * s, capryl-caprine-diglyceryl-succinate with an average viscosity of 0.23 Pa * s, medium-chain capryl-caprine-triglycerides with a viscosity of 0 , 27-0.30 Pa * s.

The formulations according to the invention may contain one or more of the above esters. Typically, the means according to the invention contain an ester or a mixture of esters in fractions comprising from 0 to 40 wt. -%, preferably from 1 to 35 wt. -%, and very preferably from 2.5 to 7.5% of the mass.

If necessary, conventional organic or inorganic antioxidants can be used to stabilize these formulations. As inorganic antioxidants, mention is made, for example, of sulfites and bisulfites, in particular sodium bisulfite. Phenolic antioxidants are preferred, such as anisole, butylhydroxytoluene and hydroxyanisole, as well as mixtures thereof with each other. Usually they are used in amounts of from 0.01 to 1% wt., Preferably from 0.05% to 0.5%, particularly preferably from 0.075 to 0.2% of the mass.

These working substances of the formulation, in particular esters, can be stabilized using an acidifier, protecting against possible hydrolytic decomposition. Pharmaceutically acceptable acids, in particular carboxylic acids, such as, for example, succinic, tartaric, lactic or citric acid, can be used as acidifying agents. Their preferred amounts are in the range from 0 to 0.5 wt. -%, mainly, however, from 0 to 0.2% of the mass.

Also, polymeric surfactants based on polymethoxysiloxanes with a low surface tension of less than 30 mN / m, more preferably less than 22 mN / m, can be used as auxiliary agents in the formulation for improving spreading. Such surfactants are known ethoxylated and / or propoxylated prescription aids, preferably neutral, or particularly preferably cationic. An example of a preferred polymeric adjuvant is Belisil Silvet L 77 methoxysilane ethylene oxide copolymer manufactured by Waueg GE Siliconics GmbH. The amount of these auxiliary prescription drugs can vary widely from 0.01 to 1.0% of the mass. The preferred range is from 0.2 to 0.4% of the mass.

If necessary, the formulations may contain other pharmaceutically acceptable excipients or additional substances.

The agents according to the invention may also contain one or more active substances as a partner of arylpyrazoles. Preferred examples of such active substances, the combination of which is advantageous, should include: growth inhibitors, such as, for example, chitin biosynthesis inhibitors, for example benzoylphenylureas (triflumuron, lufenuron), phenyloxazolines (ethoxazole), analogues of juvenile hormones (methoprene, hydroprene, pyriprox) as well as mixtures of these active substances with each other. Their amount can vary widely from 0.1 to 7.5% by weight, preferably, however, from 0.25 to 5.0% by weight, particularly preferably from 0.25 to 2.5% by weight.

The formulations according to the invention may also contain synergists. In the sense of the present application, synergists mean compounds that themselves do not have the desired effect, but when used as a component of the mixture, lead to an increase in the effectiveness of the active substances. As examples, piperonyl butoxide, MGK-264, verbutin, S, S, S-tributylphosphotrithioate should be mentioned.

The means according to the invention do not pollute the environment and have reduced toxicity compared to known means. Therefore, they are convenient to use, and are also easy to handle. The products are characterized by a favorable flash point in excess of 70 ° C, and therefore they can be manufactured using simple equipment that does not require additional measures for protection against explosions.

The agents according to the invention have favorable toxicity indicators for warm-blooded animals and are suitable for controlling parasitic arthropods, in particular insects and arachnids, in particular fleas and ticks found in animals, in particular warm-blooded, and especially mammals. This can be domestic, farm animals, animals for keeping in zoos, laboratory, experimental animals and animals that are kept as a hobby.

The agents described here are used, in particular, to combat ectoparasites in animals that are kept as a hobby, and on farm animals.

The agents according to the invention are effective against pests at all or at certain stages of development, as well as against sensitive and resistant types of pests.

Pests include:

From the order Anoplura (lice), for example Haematopinus spp., Linognathus spp., Pediculus spp., Phtirus spp., Solenopotes spp.

From the order Mallophaga (poohoedy), e.g. Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovicola spp.

From the order Diptera (dipterous), suborder Brachycera, e.g. Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., , Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp .. Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoder, spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.

From the order Diptera (dipterous), suborder Nematocera e.g. Culex spp., Aedes spp., Anopheles spp., Culicoides spp., Phlebotomus spp., Simulium spp.

From the order Siphonapterida (fleas), for example, Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp.

From the suborder Metastigmata (parasitic ticks), e.g. Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Onithodorus spp.

From the suborder Mesostigmata (gamasid mites), e.g. Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp.

From the order Prostigmata, e.g., Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.

From the Astigmata order, for example Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidocoptes spp.Cytodites spp., Lamin.

Of particular note is the efficacy against fleas (Siphonaptera, e.g., Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp.), Ticks (Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma sppis., Hemphys. spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.) and the above-mentioned dipterans (Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp.,

Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophlaga spp. ., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.).

Agricultural and breeding animals include mammals, such as cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys, rabbits, deer, reindeer, fur animals, such as minks, chinchillas, raccoons, and also birds, such as chickens, geese, turkeys, ducks.

Laboratory and experimental animals include mice, rats, guinea pigs, rabbits, golden hamsters, dogs and cats.

Animals that are kept as hobbies include dogs and cats.

Application on cats and dogs should be especially emphasized.

It can be used both for prophylactic and therapeutic purposes.

The liquid formulations according to the invention are suitable for pouring or spraying (spray), and spraying can be carried out, for example, by spray with manual injection or aerosol spray (with a blowing agent under pressure). For special indications, it is also possible to use after dilution with water in the form of a bath; in this case, the formulation should contain appropriate additives.

Preferred application forms are spray, douche, and topical exposure. Topical application by spot on.

The formulations according to the invention are characterized by excellent compatibility with conventional “one-dose” plastic tubes and storage stability in various climatic zones. They have a low viscosity and are easy to apply.

Liquid formulations according to the invention can be prepared by mixing the components with each other in appropriate quantities, for example by using conventional mixers or other appropriate devices. If the properties of the components require this, it is also possible to work in a protective atmosphere or using other methods of eliminating oxygen.

Examples:

Example 1:

100 ml liquid formulation consisting of the following components:

10.0 g 5-amino-4-trifluoromethylsulfinyl-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole 72.7 g diethylene glycol monoethyl ether 25.0 g propylene carbonate 5.0 g propylene glycol octanoate decanoate 0.1 g butylhydroxytoluene 0.2 g butylhydroxyanisole

Example 2:

100 ml liquid formulation consisting of the following components:

10.5 g fipronil 57.75 g diethylene glycol monoethyl ether 40.0 g propylene carbonate 5.0 g propylene glycol octanoate decanoate 0.1 g butylhydroxytoluene 0.2 g butylhydroxyanisole

Example 3:

100 ml liquid formulation consisting of the following components:

10.5 g fipronil 72.75 g diethylene glycol monoethyl ether 25.0 g propylene carbonate 5.0 g propylene glycol octanoate decanoate 0.1 g butylhydroxytoluene 0.2 g butylhydroxyanisole

Example 4:

100 ml liquid formulation consisting of the following components:

10.0 g 5-amino-4-trifluoromethylsulfinyl-1- (2,6-dichloro-4-trifluoromethylphenyl) -3-thiocarbamoylpyrazole 57.7 g diethylene glycol monoethyl ether 40.0 g propylene carbonate 5.0 g propylene glycol octanoate decanoate 0.1 g butylhydroxytoluene 0.2 g butylhydroxyanisole

Example 5

100 ml liquid formulation consisting of the following components:

11.4 g fipronil 60.0 g diethylene glycol monoethyl ether 25.0 g propylene carbonate 5.0 g propylene glycol octanoate decanoate 0.12 g butylhydroxytoluene 0.2 g butylhydroxyanisole 0.25 g Silvet L 77 manufactured by Bayer GE Siliconics GmbH

Test case

A 10% Spot on fipronil formulation on the market under the trademark FRONTLINE manufactured by Merial Ltd., 3239 Satellite Blvd., Duluth, GA 30096-4640, USA.

Biological Examples

Test formulations were precisely dosed by weight to improve the ability to compare data. For this, 20 pipettes of a commercial preparation containing fipronil (control example) were transferred into a glass bottle and also encrypted with a code.

All samples were applied with Eppendorf pipettes (volume up to 0.95 ml) as a separate spot on the neck of animals (cats and small dogs). If the volumes of application exceeded 1 ml, they were divided in two and applied to the neck in the form of two spots at a distance of about 10 cm from each other.

From laboratory tests for efficacy against fleas and ticks in accordance with examples 2 and 4, it follows that preparations formulated according to the above recipe according to the invention have a very strong and long-lasting effect against ticks and fleas, which, according to the test results, significantly exceeds the current technical level. In addition, the preparations formulated according to the above formulations according to the invention are distinguished by favorable tolerance indicators for the animal, on which they are used for the person carrying out the application, and thus are remarkably suitable for combating fleas and ticks that infect domestic animals. So, for example, the recipe according to example 2 after oral administration is twice as good, and the recipe according to example 4 is three times better than those of the current level of technology.

A. Effectiveness in combating fleas (Ctenocephalides felis) in dogs

In the interval between days -4 and -1, a 1-2-fold infection (infection) of dogs was carried out by adult hungry Ctenocephalides felis in the amount of 100 per dog. In this case, fleas were planted on the neck of the animal. On day 0, the effectiveness of the infestation of the dog was checked, for which they looked for fleas on an awake animal. The number of live fleas was logged.

After flea counting, animals were treated. Dogs in the control group were not treated. The drugs to be tested were applied to the skin of animals (dermal application as Spot-on) in an amount of 0.1-0.15 ml / kg body weight or sprayed with a spray in an amount of 1-1.5 ml / kg body weight. The use was carried out once on day 0. Used only clinically healthy animals. On days 1 and 2, all dogs were checked for the presence of live fleas. The results were recorded in the source data.

On days 7, 14, 21, 28, 35, and, if necessary, on days 42 and 49, re-infection (reinfestation) of all dogs with adult hungry Ctenocephalides felis was performed in an amount of about 100 per animal. The day after each reinfestation, all dogs were checked for the presence of live fleas. The results were recorded in the source data protocol.

The recipe is considered highly effective if more than 95% efficiency is recorded in the period from 24 to 48 hours after re-infection, and this effect persists for at least 3-4 weeks.

To calculate the effectiveness using a modified formula according to Abbott;

$$Effe\mathrm{to}t\mathrm{and}\mathrm{at}n\mathrm{about}\mathrm{from}tb,\%=\frac{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{TO}G-\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{ABOUT}G}{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{TO}G}\times \mathrm{one\; hundred}$$

KG: control group; OG: treated group.

The drugs in accordance with the examples of formulations 2 and 4 in the dosage examples of 0.1 or 0.15 ml / kg, applied as Spot on, have shown high efficiency in the fight against Ctenocephalides felis.

B. Effectiveness in combating ticks (Rhipicephalus sanguineus. Dermacentor variabilis) in dogs

Between days -4 and -1, the dogs were sedated by Rompun® (Bayer AG, active ingredient xylazine hydrochloride) at a concentration of 2% (0.1 ml / kg body weight). Asleep dogs (after 10-15 minutes were placed in carrying boxes and placed on the scruff of an animal 50 Rhipicephalus sanguineus or Dermacentor variabilis (25♀, 25♂) per dog. After about 1.5 hours, the animals were again transferred from the box to the cage .

On day 0, the effectiveness of the infestation of the dog was checked, for which they searched for ticks on the awake animal. At the same time, a thorough search was performed in the head and ears, including the ear fold, in the neck, lower abdomen, chest, on the sides, and also between the fingers and limbs. The number of sucking live ticks was recorded in the protocol. Dead ticks were removed.

After tick counting, animals were treated. Dogs in the control group were not treated. The drugs to be tested were applied to the skin of animals (dermal application as Spot-on) in an amount of 0.1-0.15 ml / kg body weight or sprayed with a spray in an amount of 1-1.5 ml / kg body weight. The use was carried out once on day 0. Used only clinically healthy animals. On days 1 and 2, all dogs were checked for live and dead sucking ticks. The results were recorded in the source data. On day 2, all live and dead ticks from the dog were removed. On days 7, 14, 21, 28, 35, and, if necessary, on days 42 and 49, reinfection of all dogs with adult hungry Rhipicephalus sanguineus or Dermacentor variabilis in the amount of 50 (25♀, 25♂) per dog was performed. Two days after each reinfestation, all dogs were checked for live and dead sucking ticks. The results were recorded in the source data protocol. On the second day after reinfestation, all live and dead ticks were removed from the dog.

The recipe is considered highly effective if on day 2 and on the second day after each re-infection, an efficiency of more than 90% is recorded, and this action persists for at least 3 weeks.

To calculate the effectiveness using a modified formula according to Abbott:

$$Effe\mathrm{to}t\mathrm{and}\mathrm{at}n\mathrm{about}\mathrm{from}tb,\%=\frac{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}\mathrm{to}leue\mathrm{th}\mathrm{TO}G-\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}\mathrm{to}leue\mathrm{th}\mathrm{ABOUT}G}{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}\mathrm{to}leue\mathrm{th}\mathrm{TO}G}\times \mathrm{one\; hundred}$$

KG: control group; OG: treated group.

The drugs in accordance with the examples of formulations 2 and 4 in the dosage examples of 0.1 or 0.15 ml / kg, applied as Spot on, have shown high efficiency in the fight against Rhipicephalus sanguineus.

C. Effectiveness in controlling fleas (Ctenocephalides felis) on cats

On day 1, cats were tested (infected) with adult hungry Ctenocephalides felis in an amount of about 100 per cat. In this case, fleas were planted on the neck of the animal.

On day 0, the effectiveness of the cat’s infestation was checked, for which they looked for fleas on an awake animal. The number of live fleas was logged.

After flea counting, animals were treated. Cats in the control group were not subjected to treatment. The drugs to be tested were applied to the skin of animals (dermal application as Spot-on) in an amount of 0.1-0.15 ml / kg body weight. The use was carried out once on day 0. Used only clinically healthy animals. On day 2, cats were checked for the presence of live fleas. The results were recorded in the source data.

On days 7, 14, 21, 28, 35, and, if necessary, on days 42 and 49, all cats were re-infected with adult hungry Ctenocephalides felis in an amount of about 100 per animal. Two cats were checked for live fleas after each reinfestation. The results were recorded in the source data protocol.

The recipe is considered highly effective if more than 95% efficiency is recorded on day 2 and on the second day after each re-infection, and this action persists for at least 3-4 weeks. To calculate the effectiveness using a modified formula according to Abbott:

$$Effe\mathrm{to}t\mathrm{and}\mathrm{at}n\mathrm{about}\mathrm{from}tb,\%=\frac{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{TO}G-\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{ABOUT}G}{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{TO}G}\times \mathrm{one\; hundred}$$

KG: control group; OG: treated group.

The drugs in accordance with the examples of formulations 2 and 4 in the dosage examples of 0.1 or 0.15 ml / kg, applied as Spot on, have shown high efficiency in the fight against Ctenocephalides felis.

D. Effectiveness in combating ticks (Ixodes ricinus) on cats

On the day - 2 cats were exposed to a sedative drug (acepromazine maleate). After all the cats fell asleep (after 10-15 minutes), 30-50 Ixodes ricinus (15-25♀, 15-25♂) were placed on the cat’s neck.

On day -1, the effectiveness of the cat infestation was checked, for which they searched for ticks on the awake animal. At the same time, a thorough search was carried out in the head and ears, in the neck, lower abdomen, chest, on the sides, and also on the limbs. The number of sucking live ticks was recorded in the protocol. Dead ticks were removed. After counting ticks, animals were collected in groups. Processing is carried out from day 0. Cats in the control group were not subjected to treatment. The drugs to be tested were applied to the skin of animals (dermal application as Spot-on) in an amount of 0.1-0.15 ml / kg body weight. The use was carried out once on day 0. Used only clinically healthy animals.

On day 2, cats were checked for live and dead sucking ticks. The results were recorded in the source data. All live and dead ticks were removed from the cat.

On days 7, 14, 21, 28, 35, and, if necessary, on days 42 and 49, all cats of Ixodes ricinus were re-infected in an amount of 30-50 (15-25♀, 15-25♂) per cat. Two days after each reinfestation, all cats were checked for live and dead sucking ticks. The results were recorded in the source data protocol. On the second day after reinfection, all live and dead ticks were removed from the cat.

The recipe is considered highly effective if on day 2 and on the second day after each re-infection, an efficiency of more than 90% is recorded, and this action persists for at least 3 weeks.

To calculate the effectiveness using a modified formula according to Abbott:

$$Effe\mathrm{to}t\mathrm{and}\mathrm{at}n\mathrm{about}\mathrm{from}tb,\%=\frac{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{TO}G-\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}bl\mathrm{about}x\mathrm{ABOUT}G}{\varnothing \mathrm{to}\mathrm{about}l\mathrm{and}he\mathrm{from}t\mathrm{at}\mathrm{about}\mathrm{to}leue\mathrm{th}\mathrm{TO}G}\times \mathrm{one\; hundred}$$

KG: control group; OG: treated group.

Drugs in doses according to the examples of formulations 2 and 4 in 0.1 or -0.15 ml / kg, applied as Spot on, have shown high efficiency in the fight against Ixodes ricinus.

E. Efficiency in the fight against fleas and ticks for 5-7 weeks

The effectiveness of the means according to the invention in the fight against fleas and ticks was tested for five to seven weeks. The experiments were carried out in accordance with the descriptions given in paragraphs A-D. The results are presented in tables 1a, 1b, 2a, 2b and 3.

Claims (6)

1. An agent for controlling animal parasites containing N-arylpyrazole of the general formula

where R ¹ and R ³ independently from each other mean halogen,
R ² means halogenated with 1-3 carbon atoms,
R ⁴ means a cyano group or —C (= S) NH ₂ ,
in the recipe, including:
an aliphatic cyclic carbonate, an aliphatic acyclic polyether derived from diols having up to 8 carbon atoms, and pharmaceutically acceptable excipients or additional substances. 2. The tool according to claim 1, further comprising esters of a dihydric alcohol containing up to three carbon atoms, with organic fatty acids with 6-18 carbon atoms. 3. The tool according to claim 1, containing from 1 to 27.5 wt.% N-arylpyrazole. 4. The tool according to claim 1, containing from 10 to 70 wt.% Aliphatic cyclic carbonate. 5. The tool according to one of claims 1 to 4, containing from 20 to 77.5 wt.% Aliphatic acyclic polyether. 6. The use of funds according to one of claims 1 to 5 for the manufacture of a medicinal product for combating animal parasites.